Benzimidazole compound

ABSTRACT

A benzimidazole derivative of the formula (I) or its salt: wherein A is a single bond or a C 1-2  alkylene group (this alkylene group may optionally be substituted by a C 1-4  alkyl group), R 6  is a C 1-4  alkyl group (this alkyl group may optionally be substituted by a phenyl group), B is a C 2-3  alkylene group (this alkylene group may optionally be substituted by a C 1-4  alkyl group), X is an oxygen atom, a sulfur atom or NR 7  (wherein R 7  is a nitro group, a cyano group or a C 1-4  alkoxy group), each of R 1  and R 2  which are independent of each other, is a hydrogen atom, a halogen atom, a C 1-4  alkyl group or a C 1-4  alkoxy group, E is a C 1-2  alkylene group (this alkylene group may optionally be substituted by a C 1-4  alkyl group), R 3  is a phenyl group (this phenyl group may optionally be substituted by a halogen atom, a C 1-4  alkyl group or a C 1-4  alkoxy group), a C 1-4  alkoxy group or a benzyloxy group, each of R 4  and R 5  which are independent of each other, is a C 1-4  alkyl group (this alkyl group may optionally be substituted by a phenyl group), D is a C 1-2  alkylene group (this alkylene group may optionally be substituted by a C 1-4  alkyl group), and Ar is a phenyl group.

This application is a 371 of PCT/JP98/01986 filed Apr. 30, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to a novel benzimidazole derivative havingan antiallergic activity and a drug containing it as an activeingredient.

DESCRIPTION OF THE BACKGROUND

In the treatment of type I allergy-related diseases such as pollinosis,urticaria, atopic dermatitis, allergic rhinitis and asthma,antihistamines and steroids have heretofore been frequently used.However, problems still remain with respect to the clinical usefulnessthereof. The above mentioned allergy-related diseases are triggered byan immune reaction of a specific antigen with IgE antibody and progressto a chronic state via inflammation of the diseased portion or tissuedamage. It has been suggested that during this process, various chemicalmediators are mutually closely related to the pathologic progress. Amongthem, histamine is believed to be involved mainly at the initial stageof the pathologic progress from the characteristics of itspharmacological action. This is considered to be the reason why aproblem remains with respect to the clinical usefulness ofantihistamines. On the other hand, steroids which are used primarily insevere cases, show pharmacological activities to inhibit a series ofprocesses of immuno-inflammatory responses in various fashions and arebelieved to exhibit a high level of effectiveness. However, steroidshave a problem of severe side effects, and there are many restrictionsin their application to oral administration or repeated administration.Thus, in the field of treatment of type I allergy-related diseases, itis very much desired to develop a drug having a new mechanism for actionand having a high level of effectiveness.

In recent years, it has been reported that substance P which is aneuropeptide, acts as a mediator to promote allergic symptoms and isdeeply concerned in the inflammatory symptoms particularly in thechronic phase, (TIPS, 81, 24 (1987); Am. J. Respir. Crit. Care Med.,151, 613 (1995); J. Allergy Clin. Immunol., 92, 95 (1993)). Therefore,an antagonist of substance P is considered to be capable of effectivelycuring the allergic symptoms in the chronic phase (particularly thechronic inflammation).

Substance P is a member of the neurokinin family, and it is known thatit is widely concerned in activation of macrophages or lymphocytes, andin immunity and inflammation as a regulatory factor for production ofcytokine (IL1, TNF, IL6), and it causes inflammatory symptoms such asincrease in vascular permeability, plasma leakage and secretory glandstimulation. Further, it functions as a transmitter of pain fromperipheral to central, and it controls the transmission system ofdopamine and adrenaline in brain.

Accordingly, a substance P antagonist is considered to be effective notonly as an antiallergic agent but also as analgesics or psychomimetics.

Further, a drug having not only substance P antagonistic activities butalso antihistamine activities, is considered to be effective fortreatment of a wide range of allergic symptoms ranging from acute phaseto chronic phase and thus is expected to be a drug which has clinicallyhigh curing effects.

SUMMARY OF THE INVENTION

As a result of extensive studies, the present inventors have found thatthe benzimidazole derivatives of the present invention have substance Pantagonistic activities, and further that among the compounds of thepresent invention, many also have antihistamine activities.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Benzimidazoles having antihistamine activities have already beendisclosed in e.g. JP-A-59-199679, JP-A-58-79983, EP-232937B, EP144101Band U.S. Pat. No. 4,219,559. However, the compounds of the presentinvention are not included in such disclosed benzimidazoles. Further,such prior art references disclose nothing about substance Pantagonistic activities.

Thus, it has been found that the compounds of the present invention aresuperior compounds as antiallergic agents, and they are not only usefulas active ingredients for preventive or curing agents for pollinosis,urticaria, atopic dermatitis, allergic rhinitis and asthma etc., butalso effective against other substance P related diseases, for example,eye diseases such as conjunctivitis and spring catarrh; inflammatorydiseases such as chronic rheumatoid arthritis; pains such as migraine,headache, toothache and aches accompanying various diseases;gastrointestinal diseases such as ulcerative colitis and Crohn'sdisease; and mental diseases such as depression and dysthymia. Thepresent invention has been accomplished on the basis of thesediscoveries.

The present invention provides a benzimidazole derivative of the formula(I) or its salt: ##STR1## wherein A is a single bond or a C₁₋₂ alkylenegroup (this alkylene group may optionally be substituted by a C₁₋₄ alkylgroup), R⁶ is a C₁₋₄ alkyl group (this alkyl group may optionally besubstituted by a phenyl group), B is a C₂₋₃ alkylene group (thisalkylene group may optionally be substituted by a C₁₋₄ alkyl group), Xis an oxygen atom, a sulfur atom or NR⁷ (wherein R⁷ is a nitro group, acyano group or a C₁₋₄ alkoxy group), each of R¹ and R² which areindependent of each other, is a hydrogen atom, a halogen atom, a C₁₋₄alkyl group or a C₁₋₄ alkoxy group, E is a C₁₋₂ alkylene group (thisalkylene group may optionally be substituted by a C₁₋₄ alkyl group), R³is a phenyl group (this phenyl group may optionally be substituted by ahalogen atom, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group), a C₁₋₄ alkoxygroup or a benzyloxy group, each of R⁴ and R⁵ which are independent ofeach other, is a C₁₋₄ alkyl group (this alkyl group may optionally besubstituted by a phenyl group), D is a C₁₋₂ alkylene group (thisalkylene group may optionally be substituted by a C₁₋₄ alkyl group), andAr is a phenyl group (this phenyl group may optionally be substituted bya halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group or atrifluoromethyl group), a process for its production and apharmaceutical composition containing it as an active ingredient.

Now, the substituents relating to the compound of the present inventionwill be described.

In this specification, n means normal, i iso, s secondary, t tertiary, ccyclo, Me methyl, Et ethyl, Bu butyl, Ph phenyl, and Bn benzyl.

The C₁₋₂ alkylene group includes methylene and ethylene.

The C₂₋₃ alkylene group includes ethylene and trimethylene.

The C₁₋₄ alkyl group may be linear, branched or cyclic and includesmethyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl,t-butyl and c-butyl.

The C₁₋₄ alkoxy group may be linear, branched or cyclic and includesmethoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy,s-butoxy, t-butoxy and c-butoxy.

The halogen atom includes fluorine, chlorine, bromine and iodine.

Now, A, B, D, E, Ar, X, R¹, R², R³, R⁴, R⁵ and R⁶ in the compound (I) ofthe present invention will be described in detail.

Specific examples of A include a single bond, CH₂, CHMe, CH₂ CH₂ and CH₂CHMe, preferably a single bond and CH₂.

Specific examples of B include CH₂ CH₂, CH₂ CHMe, CHMeCH₂, CHMeCHMe, CH₂CH₂ CH₂, CHMeCH₂ CH₂, CH₂ CHMeCH₂, CH₂ CH₂ CHMe, CHMeCHMeCH₂, CHMeCH₂CHMe, CH₂ CHMeCHMe and CHMeCHMeCHMe, preferably CH₂ CH₂ and CH₂ CH₂ CH₂.

Specific examples of D include CH₂, CHMe, CH₂ CH₂ and CH₂ CHMe,preferably CH₂, CHMe and CH₂ CH₂.

Specific examples of E include CH₂, CHMe, CH₂ CH₂ and CH₂ CHMe,preferably CH₂ and CH₂ CH₂.

Specific examples of Ar include phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl,4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl,2,4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibromophenyl,3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-diiodophenyl,2,4-diiodophenyl, 2,5-diiodophenyl, 2,6-diiodophenyl, 3,4-diiodophenyl,3,5-diiodophenyl, 2,3-bis(trifluoromethyl)phenyl,2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl,2,6-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl,3,5-bis(trifluoromethyl)phenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl,2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl and 2-chloro-5-trifluoromethylphenyl, preferablyphenyl, 2-chlorophenyl, 2-methoxyphenyl, 3,5-dimethylphenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,5-dichlorophenyland 2-chloro-5-trifluoromethylphenyl.

Specific examples of X include an oxygen atom, a sulfur atom, N--CN,N--NO₂, N--OMe, N--OEt and N--OBu, preferably an oxygen atom.

Specific examples of each of R¹ and R² include a hydrogen atom,fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl,c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, methoxy, ethoxy,n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxyand c-butoxy, preferably a hydrogen atom.

Specific examples of R³ include phenyl, 4-fluorophenyl, 4-chlorophenyl,methoxy, ethoxy and benzyloxy, preferably 4-fluorophenyl and ethoxy.

Specific examples of each of R⁴ and R⁵ include a hydrogen atom, methyl,ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl,c-butyl and benzyl, preferably a hydrogen atom, methyl and benzyl.

Specific examples of R⁶ include a hydrogen atom, methyl, ethyl,n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl,c-butyl and benzyl, preferably a hydrogen atom, methyl and benzyl.

The following compounds may be mentioned as preferred compounds amongthe compounds of the formula (I) of the present invention.

(1) The compound of the formula (I) or its salt, wherein A is a singlebond, CH₂, CHMe, CH₂ CH₂ or CH₂ CHMe, B is CH₂ CH₂, CH₂ CHMe, CHMeCH₂,CHMeCHMe, CH₂ CH₂ CH₂, CHMeCH₂ CH₂, CH₂ CHMeCH₂, CH₂ CH₂ CHMe,CHMeCHMeCH₂, CHMeCH₂ CHMe, CH₂ CHMeCHMe or CHMeCHMeCHMe, D is CH₂, CHMe,CH₂ CH₂ or CH₂ CHMe, E is CH₂, CHMe, CH₂ CH₂ or CH₂ CHMe, Ar is phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl,2,4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibromophenyl,3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-diiodophenyl,2,4-diiodophenyl, 2,5-diiodophenyl, 2,6-diiodophenyl, 3,4-diiodophenyl,3,5-diiodophenyl, 2,3-bis(trifluoromethyl)phenyl,2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl,2,6-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl,3,5-bis(trifluoromethyl)phenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl,2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl or 2-chloro-5-trifluoromethylphenyl, X is an oxygenatom, a sulfur atom, N--CN, N--NO₂, N--OMe, N--OEt or N--OBu, each of R¹and R² is a hydrogen atom, fluorine, chlorine, bromine, iodine, methyl,ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl,c-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy,i-butoxy, s-butoxy, t-butoxy or c-butoxy, R³ is phenyl, 4-fluorophenyl,4-chlorophenyl, methoxy, ethoxy or benzyloxy, each of R⁴ and R⁵ is ahydrogen atom, methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl,i-butyl, s-butyl, t-butyl, c-butyl or benzyl, and R⁶ is a hydrogen atom,methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl,t-butyl, c-butyl or benzyl.

(2) The compound or its salt according to the above item (1), wherein Xis an oxygen atom.

(3) The compound or its salt according to the above item (2), whereineach of R¹ and R² is a hydrogen atom.

(4) The compound of the formula (I) or its salt, wherein A is a singlebond or CH₂, B is CH₂ CH₂ or CH₂ CH₂ CH₂, D is CH₂, CHMe or CH₂ CH₂, Eis CH₂ or CH₂ CH₂, Ar is phenyl, 2-chlorophenyl, 2-methoxyphenyl,3,5-dimethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,2,5-dichlorophenyl or 2-chloro-5-trifluoromethylphenyl, X is an oxygenatom, each of R¹ and R² is a hydrogen atom, R³ is 4-fluorophenyl orethoxy, each of R⁴ and R⁵ is a hydrogen atom, methyl or benzyl, and R⁶is a hydrogen atom, methyl or benzyl.

(5) The compound or its salt according to the above item (4), wherein Eis CH₂, and R³ is a 4-fluorophenyl group.

(6) The compound or its salt according to the above item (5), wherein Aris 3,5-bistrifluoromethylphenyl.

Now, typical compounds among benzimidazole derivatives of the formula(Ia) as the compounds of the present invention will be presented inTable 1, but it should be understood that the present invention is by nomeans restricted to such specific compounds. In Table 1, Q1 to Q43represent the groups of the following formulae: ##STR2##

Further, M in the Table has the following meaning: ##STR3## wherein R⁴,R⁵ and X are as defined above.

                  TABLE 1                                                         ______________________________________                                                                      (Ia)                                                                            #STR4##                                          -                                                                          A     B      D       E    M    Ar  R.sup.1                                                                            R.sup.2                                                                             R.sup.3                                                                            R.sup.6                    ______________________________________                                        --    Q32    CH.sub.2                                                                              CH.sub.2                                                                           Q10  Q1  H    H     Q3   Me                           -- Q32 CH.sub.2 CH.sub.2 Q10 Q2 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q3 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q4 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q5 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q7 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q8 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q1 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q2 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q3 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q4 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q5 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q7 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q8 H H Q3 Me                               -- Q38 CH.sub.2 CH.sub.2 Q10 Q1 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q2 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q3 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q4 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q5 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q7 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q8 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q1 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q2 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q3 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q4 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q5 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q7 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q8 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q10 Q1 H H Ph Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q2 H H Ph Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q3 H H Ph Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q4 H H Ph Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q5 H H Ph Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Ph Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q7 H H Ph Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q8 H H Ph Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q1 H H Ph Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q2 H H Ph Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q3 H H Ph Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q4 H H Ph Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q5 H H Ph Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Ph Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q7 H H Ph Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q8 H H Ph Me                               -- Q36 CH.sub.2 CH.sub.2 Q10 Q1 H H Ph Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q2 H H Ph Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q3 H H Ph Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q4 H H Ph Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q5 H H Ph Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Ph Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q7 H H Ph Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q8 H H Ph Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q1 H H Ph Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q2 H H Ph Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q3 H H Ph Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q4 H H Ph Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q5 H H Ph Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Ph Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q7 H H Ph Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q8 H H Ph Me                               -- Q32 CH.sub.2 CH.sub.2 Q10 Q1 H H Q4 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q2 H H Q4 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q3 H H Q4 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q4 H H Q4 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q5 H H Q4 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q4 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q7 H H Q4 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q8 H H Q4 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q1 H h Q4 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q2 H H Q4 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q3 H H Q4 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q4 H H Q4 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q5 H H Q4 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q4 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q7 H H Q4 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q8 H H Q4 Me                               -- Q36 CH.sub.2 CH.sub.2 Q10 Q1 H H Q4 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q2 H H Q4 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q3 H H Q4 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q4 H H Q4 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q5 H H Q4 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q4 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q7 H H Q4 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q8 H H Q4 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q1 H H Q4 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q2 H H Q4 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q3 H H Q4 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q4 H H Q4 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q5 H H Q4 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q4 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q7 H H Q4 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q8 H H Q4 Me                               -- Q32 CH.sub.2 CH.sub.2 Q10 Q1 H H Q3 H                                      -- Q32 CH.sub.2 CH.sub.2 Q10 Q2 H H Q3 H                                      -- Q32 CH.sub.2 CH.sub.2 Q10 Q3 H H Q3 H                                      -- Q32 CH.sub.2 CH.sub.2 Q10 Q4 H H Q3 H                                      -- Q32 CH.sub.2 CH.sub.2 Q10 Q5 H H Q3 H                                      -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 H                                      -- Q32 CH.sub.2 CH.sub.2 Q10 Q7 H H Q3 H                                      -- Q32 CH.sub.2 CH.sub.2 Q10 Q8 H H Q3 H                                      CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q1 H H Q3 H                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q2 H H Q3 H                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q3 H H Q3 H                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q4 H H Q3 H                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q5 H H Q3 H                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 H                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q7 H H Q3 H                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q8 H H Q3 H                                -- Q36 CH.sub.2 CH.sub.2 Q10 Q1 H H Q3 H                                      -- Q36 CH.sub.2 CH.sub.2 Q10 Q2 H H Q3 H                                      -- Q36 CH.sub.2 CH.sub.2 Q10 Q3 H H Q3 H                                      -- Q36 CH.sub.2 CH.sub.2 Q10 Q4 H H Q3 H                                      -- Q36 CH.sub.2 CH.sub.2 Q10 Q5 H H Q3 H                                      -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 H                                      -- Q36 CH.sub.2 CH.sub.2 Q10 Q7 H H Q3 H                                      -- Q36 CH.sub.2 CH.sub.2 Q10 Q8 H H Q3 H                                      CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q1 H H Q3 H                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q2 H H Q3 H                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q3 H H Q3 H                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q4 H H Q3 H                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q5 H H Q3 H                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 H                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q7 H H Q3 H                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q8 H H Q3 H                                -- Q32 CH.sub.2 CH.sub.2 Q9 Q1 H H Q3 Me                                      -- Q32 CH.sub.2 CH.sub.2 Q9 Q2 H H Q3 Me                                      -- Q32 CH.sub.2 CH.sub.2 Q9 Q3 H H Q3 Me                                      -- Q32 CH.sub.2 CH.sub.2 Q9 Q4 H H Q3 Me                                      -- Q32 CH.sub.2 CH.sub.2 Q9 Q5 H H Q3 Me                                      -- Q32 CH.sub.2 CH.sub.2 Q9 Q6 H H Q3 Me                                      -- Q32 CH.sub.2 CH.sub.2 Q9 Q7 H H Q3 Me                                      -- Q32 CH.sub.2 CH.sub.2 Q9 Q8 H H Q3 Me                                      CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q9 Q1 H H Q3 Me                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q9 Q2 H H Q3 Me                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q9 Q3 H H Q3 Me                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q9 Q4 H H Q3 Me                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q9 Q5 H H Q3 Me                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q9 Q6 H H Q3 Me                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q9 Q7 H H Q3 Me                                CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q9 Q8 H H Q3 Me                                -- Q36 CH.sub.2 CH.sub.2 Q9 Q1 H H Q3 Me                                      -- Q36 CH.sub.2 CH.sub.2 Q9 Q2 H H Q3 Me                                      -- Q36 CH.sub.2 CH.sub.2 Q9 Q3 H H Q3 Me                                      -- Q36 CH.sub.2 CH.sub.2 Q9 Q4 H H Q3 Me                                      -- Q36 CH.sub.2 CH.sub.2 Q9 Q5 H H Q3 Me                                      -- Q36 CH.sub.2 CH.sub.2 Q9 Q6 H H Q3 Me                                      -- Q36 CH.sub.2 CH.sub.2 Q9 Q7 H H Q3 Me                                      -- Q36 CH.sub.2 CH.sub.2 Q9 Q8 H H Q3 Me                                      CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q9 Q1 H H Q3 Me                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q9 Q2 H H Q3 Me                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q9 Q3 H H Q3 Me                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q9 Q4 H H Q3 Me                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q9 Q5 H H Q3 Me                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q9 Q6 H H Q3 Me                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q9 Q7 H H Q3 Me                                CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q9 Q8 H H Q3 Me                                -- Q32 CH.sub.2 CH.sub.2 Q11 Q1 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q11 Q2 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q11 Q3 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q11 Q4 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q11 Q5 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q11 Q6 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q11 Q7 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q11 Q8 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q11 Q1 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q11 Q2 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q11 Q3 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q11 Q4 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q11 Q5 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q11 Q6 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q11 Q7 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q11 Q8 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q11 Q1 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q11 Q2 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q11 Q3 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q11 Q4 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q11 Q5 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q11 Q6 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q11 Q7 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q11 Q8 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q11 Q1 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q11 Q2 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q11 Q3 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q11 Q4 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q11 Q5 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q11 Q6 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q11 Q7 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q11 Q8 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q12 Q1 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q12 Q2 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q12 Q3 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q12 Q4 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q12 Q5 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q12 Q6 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q12 Q7 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q12 Q8 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q12 Q1 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q12 Q2 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q12 Q3 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q12 Q4 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q12 Q5 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q12 Q6 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q12 Q7 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q12 Q8 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q12 Q1 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q12 Q2 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q12 Q3 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q12 Q4 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q12 Q5 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q12 Q6 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q12 Q7 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q12 Q8 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q12 Q1 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q12 Q2 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q12 Q3 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q12 Q4 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q12 Q5 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q12 Q6 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q12 Q7 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q12 Q8 H H Q3 Me                               -- Q32 CHMe CH.sub.2 Q10 Q1 H H Q3 Me                                         -- Q32 CHMe CH.sub.2 Q10 Q2 H H Q3 Me                                         -- Q32 CHMe CH.sub.2 Q10 Q3 H H Q3 Me                                         -- Q32 CHMe CH.sub.2 Q10 Q4 H H Q3 Me                                         -- Q32 CHMe CH.sub.2 Q10 Q5 H H Q3 Me                                         -- Q32 CHMe CH.sub.2 Q10 Q6 H H Q3 Me                                         -- Q32 CHMe CH.sub.2 Q10 Q7 H H Q3 Me                                         -- Q32 CHMe CH.sub.2 Q10 Q8 H H Q3 Me                                         CH.sub.2 Q32 CHMe CH.sub.2 Q10 Q1 H H Q3 Me                                   CH.sub.2 Q32 CHMe CH.sub.2 Q10 Q2 H H Q3 Me                                   CH.sub.2 Q32 CHMe CH.sub.2 Q10 Q3 H H Q3 Me                                   CH.sub.2 Q32 CHMe CH.sub.2 Q10 Q4 H H Q3 Me                                   CH.sub.2 Q32 CHMe CH.sub.2 Q10 Q5 H H Q3 Me                                   CH.sub.2 Q32 CHMe CH.sub.2 Q10 Q6 H H Q3 Me                                   CH.sub.2 Q32 CHMe CH.sub.2 Q10 Q7 H H Q3 Me                                   CH.sub.2 Q32 CHMe CH.sub.2 Q10 Q8 H H Q3 Me                                   -- Q36 CHMe CH.sub.2 Q10 Q1 H H Q3 Me                                         -- Q36 CHMe CH.sub.2 Q10 Q2 H H Q3 Me                                         -- Q36 CHMe CH.sub.2 Q10 Q3 H H Q3 Me                                         -- Q36 CHMe CH.sub.2 Q10 Q4 H H Q3 Me                                         -- Q36 CHMe CH.sub.2 Q10 Q5 H H Q3 Me                                         -- Q36 CHMe CH.sub.2 Q10 Q6 H H Q3 Me                                         -- Q36 CHMe CH.sub.2 Q10 Q7 H H Q3 Me                                         -- Q36 CHMe CH.sub.2 Q10 Q8 H H Q3 Me                                         CH.sub.2 Q36 CHMe CH.sub.2 Q10 Q1 H H Q3 Me                                   CH.sub.2 Q36 CHMe CH.sub.2 Q10 Q2 H H Q3 Me                                   CH.sub.2 Q36 CHMe CH.sub.2 Q10 Q3 H H Q3 Me                                   CH.sub.2 Q36 CHMe CH.sub.2 Q10 Q4 H H Q3 Me                                   CH.sub.2 Q36 CHMe CH.sub.2 Q10 Q5 H H Q3 Me                                   CH.sub.2 Q36 CHMe CH.sub.2 Q10 Q6 H H Q3 Me                                   CH.sub.2 Q36 CHMe CH.sub.2 Q10 Q7 H H Q3 Me                                   CH.sub.2 Q36 CHMe CH.sub.2 Q10 Q8 H H Q3 Me                                   -- Q32 CH.sub.2 CH.sub.2 Q13 Q1 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q13 Q2 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q13 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q13 Q1 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q13 Q2 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q13 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q13 Q1 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q13 Q2 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q13 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q13 Q1 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q13 Q2 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q13 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q14 Q1 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q14 Q2 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q14 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q14 Q1 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q14 Q2 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q14 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q14 Q1 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q14 Q2 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q14 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q14 Q1 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q14 Q2 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q14 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q15 Q1 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q15 Q2 H H Q3 Me                                     -- Q32 CH.sub.2 CH.sub.2 Q15 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q15 Q1 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q15 Q2 H H Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q15 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q15 Q1 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q15 Q2 H H Q3 Me                                     -- Q36 CH.sub.2 CH.sub.2 Q15 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q15 Q1 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q15 Q2 H H Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q15 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q16 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q16 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q16 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q16 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q17 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q17 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q17 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q17 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q18 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q18 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q18 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q18 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q19 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q19 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q19 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q19 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q20 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q20 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q20 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q20 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q21 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q21 06 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q21 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q21 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q22 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q22 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q22 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q22 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q23 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q23 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q23 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q23 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q24 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q24 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q24 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q24 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q25 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q25 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q25 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q25 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q26 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q26 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q26 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q26 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q27 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q27 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q27 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q27 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q28 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q28 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q28 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q28 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q29 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q29 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q29 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q29 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q30 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q30 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q30 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q30 Q6 H H Q3 Me                               -- Q32 CH.sub.2 CH.sub.2 Q31 Q6 H H Q3 Me                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q31 Q6 H H Q3 Me                               -- Q36 CH.sub.2 CH.sub.2 Q31 Q6 H H Q3 Me                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q31 Q6 H H Q3 Me                               -- Q33 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q33 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q34 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q34 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q35 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q35 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q37 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q37 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q38 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q38 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q39 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q39 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q40 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q40 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q41 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q41 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q42 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q42 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               -- Q43 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                     CH.sub.2 Q43 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                               Q32 Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q36 CH.sub.2 CH.sub.2 Q1 Q6 H H Q3 Me                                    Q32 Q33 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q33 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q34 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q34 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q35 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q35 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q37 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q37 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q38 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q38 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q39 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q39 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q40 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q40 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q41 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q41 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q42 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q42 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   Q32 Q43 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                    CHMe Q43 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Me                                   -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Bn                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Bn                               -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Bn                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 H H Q3 Bn                               -- Q32 Q32 CH.sub.2 Q10 Q6 H H Q3 Me                                          CH.sub.2 Q32 Q32 CH.sub.2 Q10 Q6 H H Q3 Me                                    -- Q36 Q32 CH.sub.2 Q10 Q6 H H Q3 Me                                          CH.sub.2 Q36 Q32 CH.sub.2 Q10 Q6 H H Q3 Me                                    -- Q32 CH.sub.2 Q32 Q10 Q6 H H OMe Me                                         CH.sub.2 Q32 CH.sub.2 Q32 Q10 Q6 H H OMe Me                                   -- Q36 CH.sub.2 Q32 Q10 Q6 H H Ome Me                                         CH.sub.2 Q36 CH.sub.2 Q32 Q10 Q6 H H OMe Me                                   -- Q32 CH.sub.2 Q32 Q10 Q6 H H OEt Me                                         CH.sub.2 Q32 CH.sub.2 Q32 Q10 Q6 H H OEt Me                                   -- Q36 CH.sub.2 Q32 Q10 Q6 H H OEt Me                                         CH.sub.2 Q36 CH.sub.2 Q32 Q10 Q6 H H OEt Me                                   -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-F H Q3 Me                                   CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-F H Q3 Me                             -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-F H Q3 Me                                   CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-F H Q3 Me                             -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 6-F H Q3 Me                                   CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 6-F H Q3 Me                             -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 6-F H Q3 Me                                   CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 6-F H Q3 Me                             -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Cl H Q3 Me                                  CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Cl H Q3 Me                            -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Cl H Q3 Me                                  CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Cl H Q3 Me                            -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 6-Cl H Q3 Me                                  CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 6-Cl H Q3 Me                            -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 6-Cl H Q3 Me                                  CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 6-Cl H Q3 Me                            -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Br H Q3 Me                                  CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Br H Q3 Me                            -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Br H Q3 Me                                  CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Br H Q3 Me                            -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 6-Br H Q3 Me                                  CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 6-Br H Q3 Me                            -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 6-Br H Q3 Me                                  CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 6-Br H Q3 Me                            -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-F 6-F Q3 Me                                 CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-F 6-F Q3 Me                           -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-F 6-F Q3 Me                                 CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-F 6-F Q3 Me                           -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Cl 6-Cl Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Cl 6-Cl Q3 Me                         -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Cl 6-Cl Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Cl 6-Cl Q3 Me                         -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Br 6-Br Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Br 6-Br Q3 Me                         -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Br 6-Br Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Br 6-Br Q3 Me                         -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Me H Q3 Me                                  CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Me H Q3 Me                            -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Me H Q3 Me                                  CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Me H Q3 Me                            -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 6-Me H Q3 Me                                  CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 6-Me H Q3 Me                            -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 6-Me H Q3 Me                                  CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 6-Me H Q3 Me                            -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5- H Q3 Me                                          OMe                                                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5- H Q3 Me                                    OMe                                                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5- H Q3 Me                                          OMe                                                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5- H Q3 Me                                    OMe                                                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 6- H Q3 Me                                          OMe                                                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 6- H Q3 Me                                    OMe                                                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 6- H Q3 Me                                          OMe                                                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 6- H Q3 Me                                    OMe                                                                     -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Me 6-Me Q3 Me                               CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5-Me 6-Me Q3 Me                         -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Me 6-Me Q3 Me                               CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5-Me 6-Me Q3 Me                         -- Q32 CH.sub.2 CH.sub.2 Q10 Q6 5- 6-OMe Q3 Me                                      OMe                                                                     CH.sub.2 Q32 CH.sub.2 CH.sub.2 Q10 Q6 5- 6-OMe Q3 Me                                OMe                                                                     -- Q36 CH.sub.2 CH.sub.2 Q10 Q6 5- 6-OMe Q3 Me                                      OMe                                                                     CH.sub.2 Q36 CH.sub.2 CH.sub.2 Q10 Q6 5- 6-OMe Q3 Me                                OMe                                                                   ______________________________________                                    

The compound of the formula (I) of the present invention can be used forthe purpose of the present invention either in its free form or in theform of a pharmacologically acceptable salt. Such an acid addition saltmay, for example, be a mineral acid salt (such as a hydrochloride, ahydrobromide, a sulfate, a hydrogen sulfate, a nitrate, a phosphate, ahydrogen phosphate or a dihydrogen phosphate), an organic acid salt(such as a formate, an acetate, a propionate, a succinate, a malonate,an oxalate, a maleate, a fumarate, a malate, a citrate, a tartarate, alactate, a glutamate, an asparatate, a picrate or a carbonate), or asulfonate (such as a methanesulfonate, a benzenesulfonate or atoluenesulfonate).

Now, processes for the production of the compounds of the presentinvention will be described.

The benzimidazole derivatives of the formula (I) as the compounds of thepresent invention can be produced by processes represented by thefollowing reaction schemes (1) to (7). ##STR5## wherein A, B, D, E, X,Ar, X, R¹, R², R³, R⁴, R⁵ and R⁶ are as defined above, and Y is aleaving group such as a halogen atom such as a chlorine atom, a bromineatom or an iodine atom, a methanesulfonyloxy group, ap-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group.

The reaction scheme (1) is a process for producing the compound of thepresent invention by reacting a compound (IIa) with a compound (IIIa).

This reaction is carried out usually in the presence or absence of aninorganic base or an organic base.

The inorganic base includes metal carbonates such as potassiumcarbonate, sodium carbonated, lithium carbonate, potassium bicarbonateand sodium bicarbonate, metal hydroxides such as lithium hydroxide,sodium hydroxide and potassium hydroxide, metal hydrides such as sodiumhydride, potassium hydride and n-butyl lithium, metal alkoxides such assodium methoxide, sodium ethoxide and potassium t-butoxide, and metalamides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide and2,2,6,6-tetramethylpiperidide.

The organic base includes, for example, trimethylamine, triethylamine,pyridine and diisopropylethylamine.

The solvent for the reaction may be any solvent so long as it will notbe involved in the reaction, and it may, for example, be a hydrocarbontype solvent such as benzene, toluene or hexane, an ether type solventsuch as tetrahydrofuran, diethyl ether or 1,4-dioxane, an amide typesolvent such as formamide, N,N-dimethylacetamide, N,N-dimethylformamideor N-methylpyrrolidone, an alcohol type solvent such as methanol,ethanol or propanol, a halogen type solvent such as chloroform,methylene chloride or ethylene chloride, other solvent such asacetonitrile or dimethylsulfoxide, water, or a solvent mixture thereof.However, the reaction may be carried out in the absence of a solvent.

The temperature for the reaction may be within a range of from -78° C.to the boiling point of the solvent used for the reaction.

The molar ratio of the starting materials can optionally be set, but thecompound (IIIa) may be used in an amount of from 0.8 to 10 mols per molof the compound (IIa). ##STR6## wherein A, B, D, E, X, Y, Ar, R¹, R²,R³, R⁴, R⁵ and R⁶ are as defined above.

The reaction scheme (2) is a process for producing the compound of thepresent invention by reacting a compound (IIb) with a compound (IIIb).

This reaction can be carried out under conditions similar to reactionscheme (1).

The molar ratio of the starting materials can optionally be set, but thecompound (IIb) may be used in an amount of from 0.8 to 10 mols per molof the compound (IIIb). ##STR7## wherein A, B, D, E, X, Y, Ar, R¹, R²,R³, R⁴, R⁵ and R⁶ are as defined above.

The reaction scheme (3) is a process for producing the compound (I) ofthe present invention by reacting a compound (IVa) with a compound (Va).

This reaction can be carried out under conditions similar to thereaction scheme (1).

The molar ratio of the starting materials may be optionally set, but thecompound (Va) may be used in an amount of from 0.8 to 1.5 mols per molof the compound (IVa). ##STR8## wherein A, B, D, E, X, Ar, R¹, R², R³,R⁴, R⁵ and R⁶ are as defined above, and W is a halogen atom such as achlorine atom, a bromine atom or an iodine atom, an alkyl(aryl)thiogroup such as a methylthio group, a benzylthio group or a phenylthiogroup, or an alkyl(aryl)oxy group such as a methoxy group, a benzyloxygroup or a phenyloxy group.

The reaction scheme (4) is a process for producing the compound (I) ofthe present invention by reacting the compound (IVb) with a compound(Vb) or a compound (Vc). (When the compound (Vc) is employed, R⁵ in thecompound (I) will be a hydrogen atom.)

This reaction can be accomplished by heating or cooling the compound(IVb) and the compound (Vb) or the compound (IVb) and the compound (Vc),in a solvent or in the absence of a solvent, and may be carried outunder conditions similar to the reaction scheme (1).

The molar ratio of the starting materials may optionally be set, but thecompound (Vb) or the compound (Vc) may be used in an amount of from 0.8to 1.5 mols per mol of the compound (IVb). ##STR9## wherein A, B, D, E,X, W, Ar, R¹, R², R³, R⁴, R⁵ and R⁶ are as defined above.

The reaction scheme (5) is a process for producing the compound (I) ofthe present invention by reacting a compound (VIa) with a compound(VIIa).

This reaction can be accomplished by heating or cooling the compound(VIa) and the compound (VIIa) in a solvent or in the absence of asolvent, and may be carried out under conditions similar to the reactionscheme (1).

The molar ratio of the starting materials may optionally be set, but thecompound (VIa) may be used in an amount of from 0.8 to 1.5 mols per molof the compound (VIIa). ##STR10## wherein A, B, D, E, X, Y, Ar, R¹, R²,R³, R⁴, R⁵ and R⁶ are as defined above.

The reaction scheme (6) is a process for producing the compound (I) ofthe present invention by reacting a compound (VIb) with a compound(VIIb).

This reaction can be carried out under conditions similar to thereaction scheme (1).

The molar ratio of the starting materials may optionally be set, but thecompound (VIb) may be used in an amount of from 0.8 to 1.5 mols per molof the compound (VIIb). ##STR11## wherein A, B, D, E, X, Y, Ar, R¹, R²,R³, R⁴, R⁵ and R⁶ are as defined above.

The reaction scheme (7) is a process for producing the compound (I) ofthe present invention by reacting a compound (VIII) with a compound(IX).

This reaction can be carried out under conditions similar to thereaction scheme (1).

The molar ratio of the starting materials may optionally be set, but thecompound (IX) may be used in an amount of from 0.8 to 1.5 mols per molof the compound (VIII).

Now, processes for producing starting materials for the compounds of thepresent invention will be described.

Among the starting materials for the compounds of the present invention,the compound (IIa) and the compound (IIb) can be produced by theprocesses shown by the reaction scheme (8). ##STR12## wherein A, E, Y,R¹, R², R³ and R⁶ are as defined above, R⁸ is, for example, a methylgroup, a trifluoromethyl group, a phenyl group or a 4-methylphenylgroup, and Z is a protective group for an amino group, such as a formylgroup, an acetyl group, a benzyloxycarbonyl group or a t-butoxycarbonylgroup.

The compound (IIa) can be produced by condensing the compound (IIaa)with the compound (IX) to obtain the compound (IIab), followed byhalogenation (the halogenating reagent may be a chlorinating reagentsuch as phosphorus pentachloride, thionyl chloride, sulfuryl chloride,chlorine-triphenylphosphine or carbon tetrachloride-triphenylphosphine,a brominating reagent such as phosphorus tribromide, phosphoruspentabromide, thionyl bromide, sulfuryl bromide,bromine-triphenylphosphine or carbon tetrabromide-triphenylphosphine, oran iodinating reagent such as iodine-triphenylphosphine), or reacting itwith R⁸ SO₂ Cl, or by halogenating the compound (IIaa) or reacting itwith R⁸ SO₂ Cl to obtain a compound (IIac), followed by condensing itwith the compound (IX).

The compound (IIb) can be produced by reacting the compound (IIa) withthe compound (Xb) or reacting the compound (IIa) with the compound (Xa)to obtain the compound (IIbb), followed by removal of the protectivegroup, or by reacting the compound (IIac) with the compound (Xa) toobtain the compound (IIba), followed by reacting it with the compound(IX) to obtain the compound (IIbb), followed by removal of theprotective group, or conducting the removal of the protective groupfirst to obtain the compound (IIbc), followed by reacting it with thecompound (IX), or by reacting the compound (IIac) with the compound (Xb)to obtain the compound (IIbc), followed by reacting it with the compound(IX) or protecting it to obtain the compound (IIba), followed byreacting it with the compound (IX) to obtain the compound (IIbb),followed by removal of the protective group.

Among the starting materials for the compounds of the present invention,the compound (IVa) can be produced by the processes shown by thereaction scheme (9). ##STR13## wherein A, B, E, Y, R¹, R², R³, R⁶ and R⁸are as defined above.

The compound (IVa) can be produced by reacting the compound (IIa) withthe compound (XIb) or reacting the compound (IIb) with the compound(XIa) to obtain the compound (IVab), followed by halogenating it orreacting it with R⁸ SO₂ Cl, or by reacting the compound (IIac) with thecompound (XIb) or reacting the compound (IIbc) with the compound (XIa)to obtain the compound (IVaa), followed by reacting it with the compound(IX) to obtain the compound (IVab), followed by halogenating it orreacting it with R⁸ SO₂ Cl.

Among the starting materials for the compounds of the present invention,the compound (IVb) can be produced by the processes shown by thereaction scheme (10). ##STR14## wherein A, B, E, Y, Z, R¹, R², R³, R⁴and R⁶ are as defined above.

The compound (IVb) can be produced by removing the protective group ofthe compound (IVbb) or reacting the compound (IIa) with the compound(XIId). The intermediate (IVbb) can be produced by reacting the compound(IIb) with the compound (XIIb), reacting the compound (IVa) with thecompound (XIIa), reacting the compound (IVba) with the compound (IX), orreacting the compound (IIa) with the compound (XIIc).

Among the starting materials for the compounds of the present invention,the compound (VIa) can be produced by the processes shown by thereaction scheme (11). ##STR15## wherein A, B, E, X, Y, W, R¹, R², R³, R⁴and R⁶ are as defined above.

The compound (VIa) can be produced by reacting the compound (IIb) withthe compound (XIIIb), reacting the compound (IVa) with the compound(XIIIa), reacting the compound (VIaa) with the compound (IX), reactingthe compound (IIa) with the compound (XIIIc), or reacting the compound(IVb) with the compound (XIIId).

Among the starting materials for the compounds of the present invention,the compound (VIb) can be produced by the processes shown by thereaction scheme (12). ##STR16## wherein A, B, E, X, Y, W, R¹, R², R³,R⁴, R⁵ and R⁶ are as defined above.

The compound (VIb) can be produced by reacting the compound (VIa) withthe compound (XIVa), reacting the compound (IVa) with the compound(XIVb), reacting the compound (IIa) with the compound (XIVc), reactingthe compound (IIb) with the compound (XIVd), reacting the compound (IVb)with the compound (XIVe), or reacting the compound (IVba) with thecompound (IX).

Among the starting materials for the compounds of the present invention,the compound (VIII) can be produced by the processes shown by thereaction scheme (13). ##STR17## wherein A, B, D, X, Y, W, Ar, R¹, R²,R³, R⁴, R⁵, R⁶ and R⁸ are as defined above.

The compound (VIII) can be produced by reacting the compound (VIaa) withthe compound (VIIa), reacting the compound (IIac) with the compound(IIIa), reacting the compound (VIba) with the compound (VIIb), reactingthe compound (IIbc) with the compound (IIIb), removing the protectivegroup of the compound (IVba) to obtain the compound (IVbc), followed byreacting it with the compound (Vb), or halogenating the compound (IVaa)or reacting it with R⁸ SO₂ Cl to obtain the compound (IVac), followed byreacting it with the compound (Va).

The reactions of the following compounds disclosed in the reactionschemes (8) to (13), i.e. (VIaa) and (VIIa), (IIac) and (IIIa), (IIbc)and (IIIb), (VIba) and (VIIb), (IVbc) and (Vb), (IVac) and (Va), (IVb)and (XIVe), (IIb) and (XIVd), (IIa) and (XIVc), (VIa) and (XIVa), (IVa)and (XIVb), (IVa) and (XIIIa), (IIb) and (XIIIb), (IIa) and (XIIIc),(IVb) and (XIIId), (IIac) and (XIb), (IIa) and (XIb), (IIbc) and (XIa),(IIb) and (XIa), (IIb) and (XIIb), (IVa) and (XIIa), (IIa) and (XIIc),(IIa) and (XIId), (IIac) and (Xa), (IIa) and (Xa), (IIac) and (Xb),(IIa) and (Xb), (VIaa) and (IX), (VIba) and (IX), (IVba) and (IX),(IVaa) and (IX), (IIaa) and (IX), (IIac) and (IX), (IIba) and (IX), and(IIbc) and (IX), can be carried out under conditions similar to thereaction scheme (1). The reactions may be carried out also in theabsence of a solvent. The molar ratios of the compounds may beoptionally set, but they may be within a range of from 0.1:1 to 1:0.1.

The intermediates (IVba), (IVbc), (VIaa) and (VIba) disclosed in thereaction schemes (10) to (13) can be produced by the processes shown bythe reaction schemes (14) to (16). ##STR18## wherein A, B, Y, Z, R¹, R²,R⁴ and R⁶ are as defined above.

The compound (IVba) can be produced by reacting the compound (IIbc) withthe compound (XIIb), reacting the compound (IVac) with the compound(XIIa), or reacting the compound (IIac) with the compound (XIIc).

The compound (IVbc) can be produced by reacting the compound (IIac) withthe compound (XIId), or by reacting the compound (IIac) with thecompound (XIIc) to obtain the compound (IVba), followed by removing theprotective group. ##STR19## wherein A, B, X, Y, W, R¹, R², R⁴ and R⁶ areas defined above.

The compound (VIaa) can be produced by reacting the compound (IIbc) withthe compound (XIIIb), reacting the compound (IVac) with the compound(XIIIa), reacting the compound (IIac) with the compound (XIIIc), orreacting the compound (IVbc) with the compound (XIIId). ##STR20##wherein A, B, X, Y, W, R¹, R², R⁴, R⁵ and R⁶ are as defined above.

The compound (VIba) can be produced by reacting the compound (VIaa) withthe compound (XIVa), reacting the compound (IVac) with the compound(XIVb), reacting the compound (IIac) with the compound (XIVc), reactingthe compound (IIbc) with the compound (XIVd), or reacting the compound(IVbc) with the compound (XIVe).

The reactions of the following compounds disclosed in the reactionschemes (14) to (16), i.e. (IIac) and (XIIc), (IIac) and (XIId), (IIbc)and (XIIb), (IVac) and (XIIa), (IVac) and (XIIIa), (IIbc) and (XIIIb),(IIac) and (XIIIc), (IVbc) and (XIIId), (VIaa) and (XIVa), (IVac) and(XIVb), (IIac) and (XIVc), (IIbc) and (XIVd), and (IVbc) and (XIVe), canbe carried out under conditions similar to the reaction scheme (1).Further, the reactions may be carried out also in the absence of asolvent. The molar ratios of the compounds can be optionally set, butthey may be within a range of from 0.1:1 to 1:0.1.

The processes shown by the reaction scheme (17) may be employed asprocesses for producing the benzimidazole structure. ##STR21## whereinE, Y, R¹, R² and R³ are as defined above, E¹ is a single bond or amethylene group which may optionally be substituted by a C₁₋₄ alkylgroup, J is AOH, AY, ANR⁶ H, ANR⁶ Z, ANR⁶ BY, ANR⁶ BOH, ANR⁶ BNR⁴ H,ANR⁶ BNR⁴ Z, ANR⁶ BNR⁴ C(═X)W, ANR⁶ BNR⁴ C(═X)NR⁵ H or ANR⁶ BNR⁴C(═X)NR⁵ DAr (wherein A, B, D, X, Y, Z, W, Ar, R⁴, R⁵ and R⁶ are asdefined above), and G is COOH, COCl, COBr, CONH₂, CSNH₂, CHO, CN, COOR⁹(wherein R⁹ is a C₁₋₄ alkyl group, a C₁₋₄ acyl group, a phenyl group ora benzyl group), C(═NH)OR¹⁰, CH(OR¹⁰)₂ (wherein R¹⁰ is a C₁₋₄ alkylgroup, a phenyl group or a benzyl group) or CONHNHR⁹ (wherein R⁹ is asdefined above).

The benzimidazole derivative of the formula (XVc) can be prepared bycondensing the diaminobenzene derivative of the formula (XVa) with thecompound (XVI). Further, the benzimidazole derivative of the formula(XVd) can be produced by condensing the diaminobenzene derivative of theformula (XVb) with the compound (XVI), or by reacting the compound (XVc)with the compound (IX). The intermediate (XVb) can be produced byreacting the compound (XVa) with the compound (IX), or by condensing thecompound (IXa) under a reducing condition.

With respect to the production conditions, reference may be made to themethods disclosed in e.g. J. Org. Chem., 28, 1931 (1963); J. Chem. Soc.,2238 (1953); J. Am. Chem. Soc., 77, 5652 (1955); J. Chem. Soc., 673(1956); J. Am. Chem. Soc., 73, 5907 (1951); J. Am. Chem. Soc., 70, 2415(1948); J. Chem. Soc., 625, (1943); Khim. Geterotsikl. Soedin., 5, 684(1982); J. Org. Chem., 56(6), 2260 (1991); Synth. Commnn., 16(1), 35(1986); Khim. Geterotsikl. Soedin., 71 (1980); J. Chem. Soc. C., 20(1967); Chim. Ther., 2, 95 (1967); J. Org. Chem., 27, 2163 (1962); Chem.Pharm. Bull., 12, 773 (1964); J. Chem. Soc., 2296 (1959); J. Am. Chem.Soc., 79, 4391 (1957); J. Chem. Soc., 1401 (1949).

By the above processes, the compounds (IIaa), (IIac), (IIbc), (IIba),(IVac), (IVaa), (IVbc), (IVba), (VIaa), (VIba) and (VIII) may beproduced directly from the compound (XVa). Further, the compounds(IIab), (IIa), (IIb), (IIbb), (IVa), (IVab), (IVbb), (IVb), (VIa), (VIb)and (I) may be produced directly from the compound (XVb).

For the production of the compounds (XVa) and (XVb), the processes shownin the reaction scheme (18) may be employed. ##STR22## wherein E, Y, R¹,R² and R³ are as defined above.

The compound (XVa) can be produced by reacting the compound (XVIIa) withammonia to obtain the compound (XVIIb), followed by reducing it.Further, the compound (XVb) can be produced by reacting the compound(XVIIa) with the compound (IXb) to obtain the compound (XVIIc), followedby reducing it.

As described in the foregoing, the present inventors have found that thecompound of the formula (I) of the present invention is a superiorcompound as a strong antiallergic agent, and it is not only useful as anactive ingredient for a preventive or curing agent for pollinosis,urticaria, atopic dermatitis, allergic rhinitis and asthma etc., butalso effective against other substance P related diseases, for example,eye diseases such as conjunctivitis and spring catarrh; inflammatorydiseases such as chronic rheumatoid arthritis; pains such as migraine,headache, toothache and aches accompanying various diseases;gastrointestinal diseases such as ulcerative colitis and Crohn'sdisease; and mental diseases such as depression and dysthymia. Thus, thepresent invention provides a pharmaceutical composition containing thecompound of the present invention in an amount effective for treatmentof these diseases.

The mode of administration of the compound of the present invention maybe parenteral administration of an injection (hypodermic, intravenous,intramuscular or intraperitoneal injection), an ointment, a suppositoryor an aerosol or oral administration of tablets, capsules, granules,pills, a syrup, a liquid, an emulsion or a suspension.

The pharmacological or veterinary composition containing a compound ofthe present invention contains the compound of the present invention inan amount of from about 0.01 to 99.5%, preferably from about 0.1 to 30%,based on the total weight of the composition.

In addition to the compound of the present invention, otherpharmacological or veterinary active compound may be incorporated intothe composition. Such a composition may contain a plurality of compoundsof the present invention.

The effective dose of the compound of the present invention is usuallyfrom about 0.003 to 1.5 g, preferably from about 0.01 to 0.6 g, per anadult per day, although its clinical dose depends on the age, weight,sensitivity and condition of the patient. However, if necessary, thedose may be out of the above-mentioned range.

The compounds of the present invention may be formulated into variousformulations suitable for administration in accordance withpharmaceutically conventional methods.

Namely, tablets, capsules, granules or pills for oral administration,may be prepared by using an excipient such as sugar, lactose, glucose,starch or mannitol; a binder such as hydroxypropylcellulose, syrup, gumarabic, gelatin, sorbitol, tragacanth gum, methylcellulose orpolyvinylpyrrolidone; a disintegrant such as starch,carboxymethylcellulose or its calcium salt, microcrystalline celluloseor polyethylene glycol; a gloss agent such as talc, magnesium or calciumstearate or silica; or a lubricant such as sodium laurate or glycerol.

Injections, solutions, emulsions, suspensions, syrups or aerosols, maybe prepared by using a solvent for the active ingredient such as water,ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycolor polyethylene glycol; a surfactant such as a sorbitan fatty acidester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylenefatty acid ester, a polyoxyethylene ether of hydrogenated castor oil orlecithin; a suspending agent such as a cellulose derivative such as asodium salt of carboxymethyl or methylcellulose, or a natural rubbersuch as tragacanth gum or gum arabic; or a preservative such as aparaoxybenzoic acid ester, benzalkonium chloride or a salt of sorbicacid.

Ointments for percutaneous absorption may be prepared by using whitesoft paraffin, liquid paraffin, a higher alcohol, macrogol ointment,hydrophilic ointment or an aqueous gel-type vehicle.

Suppositories may be prepared by using e.g. cacao butter, polyethyleneglycol, lanolin, fatty acid triglyceride, coconut butter or polysorbate.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLES

Now, the present invention will be described in further detail withreference to Examples (including Preparation Examples, FormulationExamples and Test Examples). However, it should be understood that thepresent invention is by no means restricted by these specific Examples.

The symbol "m.p." indicates "melting point".

Reference Example 1N-methyl-N-(benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine

A solution comprising 1.1 g of 2-chlorobenzimidazole and 1.6 g ofN,N'-dimethyl-1,3-propylenediamine was heated at a temperature of from120 to 130° C. for two hours. After cooling, the solution was dilutedwith 50 ml of chloroform and washed with 30 ml of a 1 N potassiumcarbonate aqueous solution. It was dried over anhydrous sodium sulfate,and then the solvent was distilled under reduced pressure. The obtainedresidue was dissolved in 50 ml of chloroform, and 5 g of di-t-butyldicarbonate was added thereto. The mixture was left to stand at roomtemperature for one hour, and then the solvent was distilled off underreduced pressure. The obtained residue was crystallized from diethylether to obtain 2.1 g of the above identified compound as pale browncrystals.

Reference Example 2N-methyl-N-(benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,2-ethylenediamine

In the same manner as in Reference Example 1, 1.1 g of the aboveidentified compound was obtained as pale brown crystals, from 1.0 g of2-chlorobenzimidazole and 4.0 g of N,N'-dimethyl-1,2-ethylenediamine.

Reference Example 3N-methyl-N-(benzimidazol-2-yl)methyl-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine

4.0 g of 2-chloromethylbenzimidazole was added under cooling with ice toa solution comprising 5.0 g of N,N'-dimethyl-1,3-propylenediamine and 30ml of ethanol, and the mixture was stirred for one hour. The mixture wasreturned to room temperature and stirred overnight, whereupon thesolvent was distilled off under reduced pressure. To the obtainedresidue, 50 ml of water and 50 ml of chloroform were added, andpotassium carbonate was added until the mixture became basic. Theorganic layer was taken and dried over anhydrous potassium sulfate, andthen, the solvent was distilled off under reduced pressure. To theobtained residue, 50 ml of chloroform was added, and 8 g of di-t-butyldicarbonate was added to this solution. The mixture was stirred at roomtemperature for one hour, and then the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (eluent: ethyl acetate/ethanol=9/1) to obtain 7.0 g ofthe above identified compound as a brown oily substance.

Reference Example 4N-methyl-N-(benzimidazol-2-yl)methyl-N'-methyl-N'-t-butoxycarbonyl-1,2-ethylenediamine

In the same manner as in Reference Example 3, 6.5 g of the aboveidentified compound was obtained as a orange colored oily substance from8.0 g of N,N'-dimethyl-1,2-ethylenediamine and 5.0 g of2-chloromethylbenzimidazole.

Reference Example 5N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine

A solution comprising 1.0 g ofN-methyl-N-(benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine,540 mg of 4-fluorobenzyl chloride, 3 g of potassium carbonate and 20 mlof dimethylformamide, was reacted at room temperature overnight under astirring condition. Further, it was reacted at a temperature of from 50to 60° C. for 10 hours. Then, 50 ml of water was added thereto, and themixture was extracted with ethyl acetate. The extract was dried overanhydrous sodium sulfate (30 ml×3), and then, the solvent was distilledoff under reduced pressure. The obtained residue was purified by silicagel column chromatography (eluent: ethyl acetate) to obtain 1.4 g of theabove identified compound as a colorless oily substance.

Reference Example 6N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,2-ethylenediamine

In the same manner as in Reference Example 5, 1.3 g of the aboveidentified compound was obtained as a pale yellow oily substance from1.0 g ofN-methyl-N-(benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,2-ethylenediamine.

Reference Example 7N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)methyl-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine

In the same manner as in Reference Example 5, 5.0 g of the aboveidentified compound was obtained as a pale yellow oily substance from6.5 g ofN-methyl-N-(benzimidazol-2-yl)methyl-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine.

Reference Example 8N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)methyl-N'-methyl-N'-t-butoxycarbonyl-1,2-ethylenediamine

In the same manner as in Reference Example 5, 6.1 g of the aboveidentified compound was obtained as a pale yellow oily substance from6.0 g ofN-methyl-N-(benzimidazol-2-yl)methyl-N'-methyl-N'-t-butoxycarbonyl-1,2-ethylenediamine.

Preparation Example 1N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)-N'-methyl-N'-(3,5-bis(trifluoromethyl)benzylaminocarbonyl)-1,3-propylenediaminehydrochloride

2 ml of trifluoroacetic acid was added to 1.3 g ofN-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine,and the mixture was stirred at room temperature for one hour. Then, 50ml of water and 50 ml of chloroform were added thereto, and potassiumcarbonate was added thereto until the mixture became basic. The organiclayer was taken and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, to obtain 970 mg of a colorlessoily substance. To 300 mg of this oily substance, 370 mg of phenylN-(3,5-bis(trifluoromethyl)benzyl)carbamate was added, and the mixturewas heated and stirred at 120° C. for two hours. After cooling, theobtained oily substance was purified by silica gel column chromatography(eluent: ethyl acetate/ethanol=9/1) to obtain 500 mg of a colorless oilysubstance. 250 mg of this oily substance was dissolved in 3 ml ofethanol, and 1 ml of 28% hydrochloric acid-ethanol was added thereto.The solvent was distilled off under reduced pressure, and the residuewas crystallized from diethyl ether to obtain 280 mg of the aboveidentified compound as colorless crystals. (m.p. 170.0-172.0° C.)

Preparation Example 2N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)-N'-methyl-N'-(3,5-bis(trifluoromethyl)benzylaminocarbonyl)-1,2-ethylenediaminehydrochloride

In the same manner as in Preparation Example 1, the above identifiedcompound was obtained as colorless crystals fromN-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,2-ethylenediamine.(m.p. 182.0-185.0° C.)

Preparation Example 3N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)methyl-N'-methyl-N'-(3,5-bis(trifluoromethyl)benzylaminocarbonyl)-1,3-propylenediaminehydrochloride

In the same manner as in Preparation Example 1, the above identifiedcompound was obtained as a pale yellow oily substance fromN-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)methyl-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine.

Preparation Example 4N-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)methyl-N'-methyl-N'-(3,5-bis(trifluoromethyl)benzylaminocarbonyl)-1,2-ethylenediaminehydrochloride

In the same manner as in Preparation Example 1, the above identifiedcompound was obtained as colorless crystals fromN-methyl-N-(1-(4-fluorobenzyl)benzimidazol-2-yl)methyl-N'-methyl-N'-t-butoxycarbonyl-1,2-ethylenediamine.(m.p. 144.0-145.0° C.)

Preparation Examples 5 to 13

In the same manner as in Preparation Example 1, the compounds shown inTable 2 were prepared in the form of their hydrochlorides.

                  TABLE 2                                                         ______________________________________                                          #STR23##                                                                      Example                      m.p.                                             No. R (° C.)                                                         ______________________________________                                           5                                                                                                       197.0 ##                                            -  6                                                                                                    211.0 ##                                            -  7                                                                                                    184.0 ##                                            -  8                                                                                                    139.0 ##                                            -  9                                                                                                    175.0-178.0                                         - 10                                                                                                    138.0 ##                                            - 11                                                                                                    156.0-159.0                                         - 12                                                                                                    176.0 ##                                            - 13                                                                                                    178.62##                                         ______________________________________                                    

    ______________________________________                                        FORMULATION EXAMPLE 1                                                           Tablets                                                                     ______________________________________                                        Compound of the present invention                                                                   10 g                                                      Lactose 260 g                                                                 Microcrystalline cellulose 600 g                                              Corn starch 350 g                                                             Hydroxypropyl cellulose 100 g                                                 CMC-Ca 150 g                                                                  Magnesium stearate  30 g                                                      Total 1,500 g                                                               ______________________________________                                    

The above ingredients were mixed by a conventional method and made into10,000 sugar coated tablets containing 1 mg of the active ingredient pertablet.

    ______________________________________                                        FORMULATION EXAMPLE 2                                                           Capsules                                                                    ______________________________________                                        Compound of the present invention                                                                  10 g                                                       Lactose 440 g                                                                 Microcrystalline cellulose 1,000 g                                            Magnesium stearate 50 g                                                       Total 1,500 g                                                               ______________________________________                                    

The above ingredients were mixed by a conventional method and stuffedinto gelatin capsules to obtain 10,000 capsules containing 1 mg of theactive ingredient per capsule.

    ______________________________________                                        FORMULATION EXAMPLE 3                                                           Soft elastic capsules                                                       ______________________________________                                        Compound of the present invention                                                                  10 g                                                       PEG 400 479 g                                                                 Saturated fatty acid triglyceride 1,500 g                                     Peppermint oil  1 g                                                           Polysorbate 80 10 g                                                           Total 2,000 g                                                               ______________________________________                                    

The above ingredients were mixed and then stuffed into No. 3 softgelatin capsules by a conventional method to obtain 10,000 soft elasticcapsules containing 1 mg of the active ingredient per capsule.

    ______________________________________                                        FORMULATION EXAMPLE 4                                                           Ointment                                                                    ______________________________________                                        Compound of the present invention                                                                   1.0 g                                                     Liquid paraffin 10.0 g                                                        Cetanol 20.0 g                                                                White soft paraffin 68.4 g                                                    Ethyl paraben  0.1 g                                                          1-menthol  0.5 g                                                              Total 100.0 g                                                               ______________________________________                                    

The above ingredients were mixed by a conventional method to obtain 1%ointment.

    ______________________________________                                        FORMULATION EXAMPLE: 5                                                          Suppository                                                                 ______________________________________                                        Compound of the present invention                                                                   1 g                                                       Witepsol H15* 478 g                                                           Witepsol W35* 520 g                                                           Polysorbate 80  1 g                                                           Total 1,000 g                                                               ______________________________________                                         *Tradename for a triglyceride type compound                              

The above ingredients were melti-mixed by a conventional method andpoured into a suppository container, followed by cooling andsolidification to obtain 1,000 pieces of a 1 g suppository containing 1mg of the active ingredient.

    ______________________________________                                        FORMULATION EXAMPLE 6                                                           Injection                                                                   ______________________________________                                        Compound of the present invention                                                                  1 mg                                                       Distilled water for injection 5 ml                                          ______________________________________                                    

Whenever required, the injection is prepared by dissolving the compoundin the distilled water.

TEST EXAMPLES

Inhibitory effect on substance P and histamine-induced contraction ofthe isolated guinea-pig ileum.

Compound

Test compounds were dissolved and diluted in 100% dimethylsulfoxide(DMSO). Substance P (SP, Peninsula Laboratories or Peptide Institute)and histamine dihydrochloride (Wako Pure Chemicals) were dissolved anddiluted in distilled water. DMSO in organ bath did not exceed 0.25% v/v.

Methods

Male Hartley guinea-pigs (300-400 g) were killed by a blow to the head.The ileum was removed and the ileal strips (15-20 mm) were suspendedunder 0.5 g tension in a 20 ml organ bath containing a modified Tyrodesolution maintained at 30° C. and aerated with 95% O₂ +5% CO₂. Responseswere recorded isotonically. Tissues were equilibrated for 15 min, andthen the constant responses to histamine (1 μM) were obtained. Thensubstance P (0.01 μM) or histamine (0.1 μM)-induced contraction wasobtained after 5 min incubation with or without the test compounds.Contractile responses to substance P or histamine with the test compoundwere expressed as a percentage of those without the test compound. IC₅₀was the concentration of the test compound required to prevent 50% ofthe contractile response elicited by substance P or histamine. CompoundNos. of the tested compounds correspond to the numbers of PreparationExamples.

    ______________________________________                                        Tested         IC.sub.50 (μM)                                              compounds      Substance P                                                                             Histamine                                            ______________________________________                                        1              0.59      0.29                                                   2 2.8 1.1                                                                     3 1.4 0.16                                                                    4 0.95 0.10                                                                   5 3.0 0.029                                                                   6 2.7 0.025                                                                   7 4.0 0.10                                                                    8 3.0 0.28                                                                    9 2.7 0.036                                                                   10 2.8 0.041                                                                  11 1.5 0.20                                                                   12 4.1 0.044                                                                  13 2.8 0.028                                                                ______________________________________                                    

The compounds of the present invention exhibit antagonistic activitiesagainst substance P, and they are useful as anti-allergic agents.

What is claimed is:
 1. A benzimidazole compound of the formula (I) or a salt thereof: ##STR33## wherein A is a single bond or C₁₋₂ alkylene, which is optionally substituted by C₁₋₄ alkyl; R⁶ is hydrogen, C₁₋₄ alkyl, which is optionally substituted by phenyl; B is C₂₋₃ alkylene, which is optionally substituted by C₁₋₄ alkyl; X is oxygen, sulfur, or NR⁷, wherein R⁷ is nitro, cyano or C₁₋₄ alkoxy; each of R¹ and R² which are independent of each other, is hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; E is C₁₋₂ alkylene, which is optionally substituted by C₁₋₄ alkyl; R³ is phenyl, which is optionally substituted by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy, C₁₋₄ alkoxy or benzyloxy; each of R⁴ and R⁵ which are independent of each other, is hydrogen, C₁₋₄ alkyl, which is optionally substituted by phenyl; D is C₁₋₂ alkylene, which is optionally substituted by C₁₋₄ alkyl; and Ar is phenyl which is, optionally substituted by halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl.
 2. The compound or the salt thereof of claim 1, wherein A is a single bond, CH₂, CHMe, CH₂ CH₂ or CH₂ CHMe; B is CH₂ CH₂, CH₂ CHMe, CHMeCH₂, CHMeCHMe, CH₂ CH₂ CH₂, CHMeCH₂ CH₂, CH₂ CHMeCH₂, CH₂ CH₂ CHMe, CHMeCHMeCH₂, CHMeCH₂ CHMe, CH₂ CHMeCHMe or CHMeCHMeCHMe; D is CH₂, CHMe, CH₂ CH₂ or CH₂ CHMe; E is CH₂, CHMe, CH₂ CH₂ or CH₂ CHMe; Ar is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-diiodophenyl, 2,4-diiodophenyl, 2,5-diiodophenyl, 2,6-diiodophenyl, 3,4-diiodophenyl, 3,5-diiodophenyl, 2,3-bis(trifluoromethyl)phenyl, 2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl, 2,6-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl or 2-chloro-5-trifluoromethylphenyl, X is an oxygen atom, a sulfur atom, N--CN, N--NO₂, N--OMe, N--OE or N--OBu, each of R¹ and R² is a hydrogen atom, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, or c-butoxy, R³ is phenyl, 4-fluorophenyl, 4-chlorophenyl, methoxy, ethoxy or benzyloxy, each of R⁴ and R⁵ is a hydrogen atom, methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl or benzyl, and R⁶ is a hydrogen atom, methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl or benzyl.
 3. The compound or the salt thereof of claim 2, wherein X is oxygen.
 4. The compound or the salt thereof of claim 3, wherein each of R¹ and R² is hydrogen.
 5. The compound or the salt thereof of claim 2, wherein A is a single bond or CH₂ ; B is CH₂ CH₂ or CH₂ CH₂ CH₂ ; D is CH₂, CHMe or CH₂ CH₂ ; E is CH₂ or CH₂ CH₂ ; Ar is phenyl, 2-chlorophenyl, 2-methoxyphenyl, 3,5-dimethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,5-bis(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,5-dichlorophenyl or 2-chloro-5-trifluoromethylphenyl; X is oxygen; each of R¹ and R² is hydrogen; R³ is 4-fluorophenyl or ethoxy; each of R⁴ and R⁵ is hydrogen, methyl or benzyl; and R⁶ is hydrogen, methyl or benzyl.
 6. The compound or the salt thereof of claim 5, wherein E is CH₂ ; and R³ is a 4-fluorophenyl group.
 7. The compound or the salt thereof of claim 6, wherein Ar is 3,5-bis(trifluoromethyl)phenyl.
 8. The compound or the salt thereof of claim 6, which is selected from the group consisting of N-methyl-N-(1-(4-fluorobenzyl)benzionidazol-2-yl)-N'-methyl-N-(3,5-bis(trifluoromethyl)benzylaminocarbonyl)-1,3-propylenediamine hydrochloride, N-methyl-N-(1-(4-fluorobenzyl)benzimidozol-2-yl)-N'-methyl-N'-(3,5-bis(trifluoromethyl)benzylaminocarbonyl)-1,2-ethylenedianine hydrochloride, N-methyl-N-(1-(4-fluorobenzyl)benzimidozol-2-yl)methyl-N'-methyl-N'-(3,5-bis(trifluoromethyl)benzylaminocarbonyl)-1,3-propylenediamine hydrochloride, and N-methyl-N(1-(4-fluorobenzyl)benzimidozol-2-yl)methyl-N'-methyl-N'-(3,5-bis(trifluoromethyl)benzylaminocarbonyl)-1,2-ethylinediamine hydrochloride.
 9. The compound or the salt thereof claim 6, which has the formula: ##STR34## wherein R is selected from the group consisting of ##STR35##10.
 10. A pharmaceutical composition, which comprises an effective amount of the compound or the salt thereof of claim 2, and a pharmaceutically acceptable salt thereof. 